Is early detection of keratoconus worthwhile? Systematic ...€¦ · Organization principles of screening are used as a guideline. Methods: A systematic review of the Pubmed, Cochrane

Academiejaar 2018 – 2019

Is early detection of keratoconus worthwhile?

Systematic review based on the WHO criteria for

screening.

Sandra VERMEIRSCH

Promotors: Prof. Dr. I. Claerhout, Dr. E. Kreps

Masterproef voorgedragen in de master in de specialistische geneeskunde Oftalmologie

Academiejaar 2018 – 2019

Is early detection of keratoconus worthwhile?

Systematic Review based on the WHO criteria for

screening.

Sandra VERMEIRSCH

Promotors: Prof. Dr. I. Claerhout, Dr. E. Kreps

Masterproef voorgedragen in de master in de specialistische geneeskunde Oftalmologie

Table of content

Abstract ...................................................................................................................................... 1

1. Introduction ........................................................................................................................ 2

1.a. Introduction on keratoconus ............................................................................................ 2

1.b. Purpose ............................................................................................................................ 4

2. Methods .............................................................................................................................. 5

3. Results ................................................................................................................................ 6

3.a. The condition sought should be an important health problem ........................................ 6

3.a.1. Prevalence and incidence ......................................................................................... 6

3.a.2. Quality of life ........................................................................................................... 8

3.a.3. Discussion ................................................................................................................. 9

3.b. The natural history of the condition, including development from latent to declared

disease, should be adequately understood ............................................................................ 10

3.b.1. Demographics and natural progression .................................................................. 10

3.b.2. Risk factors ............................................................................................................. 12

3.b.3. Development from latent to declared disease......................................................... 13

3.b.4. Discussion .............................................................................................................. 13

3.c. There should be a recognizable latent or early symptomatic stage ............................... 14

3.d. There should be a suitable test or examination ............................................................. 15

3.e. The test should be acceptable to the population ............................................................ 15

3.f. There should be an agreed policy on whom to treat as patients .................................... 15

3.g. There should be an accepted treatment for patients with keratoconus .......................... 16

3.g.1. Treatment options to improve visual acuity ........................................................... 16

3.g.2. Treatment option to stabilize progression: Corneal cross-linking (CXL) .............. 18

3.g.3. Discussion .............................................................................................................. 21

3.h. Facilities for diagnosis and treatment should be available ............................................ 22

3.i. The cost of case-finding (including diagnosis and treatment of patients diagnosed) should

be economically balanced in relation to possible expenditure on medical care as a whole . 23

3.i.a. Societies’ point of view ........................................................................................... 23

3.i.b. Patients’ point of view ............................................................................................ 24

3.i.c. Discussion ............................................................................................................... 24

3.j. Case-finding should be a continuing process and not a “once and for all” project........ 25

4. Final discussion ................................................................................................................ 27

Dutch summary ........................................................................................................................ 28

Addendum 1: Search strategy

Addendum 2: JBI Critical Appraisal Tool for Quality assessment of articles

Bibliography

Abbreviations

AC Allergic Conjunctivitis

ARC Anterior Radius of Curvature

ARMD Age-Related Macular Degeneration

BAD-D Belin/Ambrosio Enhanced Ectasia Total Derivation Value

BCVA Best-Corrected Visual Acuity

BDVA Best-Corrected Distance Visual Acuity

BSCVA Best Spectacle-Corrected Visual Acuity

Can$ Canadian Dollars

CAT Critical Appraisal Tool

CB Chronic Blepharitis

CCT Central Corneal Thickness

CL Contact Lens(es)

CLEK Collaborative Longitudinal Evaluation of Keratoconus

CSC Cataract Surgical Coverage

CSR Cataract Surgical Rate

CXL Cross-linking

D Diopter(s)

DALK Deep Anterior Lamellar Keratoplasty

DM Diabetes Mellitus

DRP Diabetic Retinopathy

DUSKS Dundee University Scottish Keratoconus Study

GDP Gross Domestic Product

HDI Human Development Index

HR High Resolution

ICER Incremental Cost-Effectiveness Ratio

ICRS Intrastromal Corneal Ring Segments

ISV Index of Surface Variance

IVA Index of Vertical Asymmetry

JBI Joanna Briggs Institute

KC Keratoconus

KPI Keratoconus Prediction Index

LASIK Laser In Situ Keratomileusis

NEI-VFQ-25 National Eye Institute-Vision Function Questionnaire

NS Not Specified

OSA Obstructive Sleep Apnea

PK Penetrating Keratoplasty

PRC Posterior Radius of Curvature

PRISMA Preferred Reporting Items for Systematic reviews and Meta-Analyses

PRK Photorefractive Keratectomy

QALY Quality-Adjusted Life Years

QoL Quality of Life

RGP Rigid Gas Permeable contact lenses

SE Spherical Equivalent

t-PRK Topography-guided Photorefractive Keratectomy

UCVA Uncorrected Visual Acuity

UK United Kingdom

USA United States of America

US$ United States Dollar

UVA Ultraviolet A

VA Visual Acuity

VKC Vernal Keractoconjunctivitis

WHO World Health Organization

1

Abstract

Purpose: To research whether screening for keratoconus is worthwhile, based on the

current evidence for early detection and treatment of keratoconus. The World Health

Organization principles of screening are used as a guideline.

Methods: A systematic review of the Pubmed, Cochrane and Web of Science databases,

according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)

guidelines.

Results: Recent reports suggest that the prevalence of keratoconus is substantially higher

than previously thought. While keratoconus does not result in blindness, it does cause

significant morbidity as it is a chronic eye disease affecting young, economically active

patients, with a significant impact on the quality of life. The magnitude of the public health

impact of keratoconus is disproportionate to its prevalence and clinical severity, and has an

important impact on public health budget.

Corneal imaging techniques have greatly improved, enabling us to diagnose keratoconus in a

subclinical stage. The ultimate goal of treating patients with keratoconus is to preserve or even

improve their quality of life, and to improve their ability to perform visually related tasks. Even

though no definite treatment is available, the introduction of corneal cross-linking in the early

2000s has revolutionized the care for keratoconus patients. Whereas in the past merely methods

for optical correction were available, corneal cross-linking has proven to halt progression in

keratoconus, thus reducing the need for corneal transplantation. Moreover, cross-linking has

been proven to be cost-effective.

Conclusion: Early and reliable detection of keratoconus is required to fully utilize the benefits

provided by stabilization of disease progression. Currently, insufficient data are available to

estimate the possible effects and costs of a screening program. Further research - investigating

the feasibility and (cost-)effectiveness of various screening strategies for keratoconus - is

necessary to maximize the benefits of corneal cross-linking.

2

1. Introduction

1.a. Introduction on keratoconus

Keratoconus (KC) is a bilateral, yet asymmetrical chronic corneal disease, that affects patients

in their puberty or early adulthood. The cornea becomes ectatic and assumes a conical shape,

which is accompanied by stromal thinning. This leads to irregular astigmatism, myopia, and

corneal protrusion. With progressing stromal thinning, this can evolve to a loss of correlation

between the anterior and posterior corneal curvature.

Clinical signs depend on the stage of disease and include conical protrusion, an iron deposition

line surrounding the base of the cone (Fleischer ring), and fine vertical lines in the deep stroma

and Descemet membrane (Vogt striae). In advanced stages, sudden breaks in Descemet

membrane can lead to stromal imbibition of aqueous, a condition referred to as acute hydrops,

and corneal scarring can occur. (1, 2) The progressive change in corneal shape prompts vision

loss and can influence vision-related quality of life (QoL).(3)

The exact etiology of keratoconus remains unknown, yet it’s widely accepted that it is a

complex multifactorial disorder with environmental, biomechanical and genetic factors playing

a role. Common risk factors are eye rubbing, atopic disease, family history of keratoconus,

Down syndrome and connective tissue disorders.(4, 5)

The gold standard for the diagnosis of keratoconus is corneal topography (or tomography). An

asymmetrical bowtie pattern (contrary to the symmetrical bowtie in regular astigmatism), high

astigmatism or a conical shape should alert the examiner to the possible diagnosis of

keratoconus. Different indices have been developed that differentiate keratoconic from normal

corneas: commonly used indices are the central K value (calculated by averaging the dioptric

power on rings 2-4 of the placido disc), inferior-superior (I-S) index (calculated by comparing

the difference in dioptric power between points on the inferior cornea with corresponding points

on the superior cornea), KISA% index (derived and calculated from 4 indices), and keratoconus

prediction index (KPI, derived and calculated from 8 indices).(1, 6, 7) Frequently used

diagnostic devices are based on slit-scanning elevation topography (e.g. Orbscan; Bausch and

Lomb Surgical, USA), and Scheimpflug imaging techniques (e.g. Pentacam HR tomography;

Oculus, Germany).(8, 9) With the Pentacam HR, combined factors and indices can be displayed

as the Belin Ambrosio Enhanced Ectasia Display, or the Holladay 6 map display to facilitate

quick and effective screening of ectatic disease.(1, 10)

3

Commonly used classification systems are the Amsler-Krumeich classification(1) (cfr. Table

1A), and the newer ABCD-grading system(11) (cfr Table 1B).

Table 1A: the Amsler-Krumeich classification

Stage Findings

I Eccentric steepening

Myopia, induced astigmatism, or both <5.00 diopter (D)

Mean central K readings <48 D

II Myopia, induced astigmatism, or both from 5.00 to 8.00 D

Mean central K readings <53.00 D

Absence of scarring

Corneal thickness >400 micron

III Myopia, induced astigmatism, or both from 8.00 to 10.00 D

Mean central K readings >53.00 D

Absence of scarring

Corneal thickness 300-400 micron

IV Refraction not measurable

Mean central K readings >55.00 D

Central corneal scarring

Corneal thickness < 200 micron

Table 1B: ABCD-grading system for keratoconus

A (ARC) ° B (PRC) * C (pachy) † D (BDVA) °° Scarring

Stage 0 >7.25 mm (<46.5D) >5.90 mm (<57.25D) >490 >20/20 -

Stage 1 >7.05 mm (<48.0D) >5.70 mm (<59.25D) >450 >20/20 -, +, ++

Stage 2 >6.35 mm (<53.0D) >5.15 mm (<65.5D) >400 <20/40 -, +, ++

Stage 3 >6.15 mm (<55.0D) >4.95 mm (<68.5D) >300 <20/100 -, +, ++

Stage 4 <6.15 mm (>55.0D) <4.95 mm (>68.5D) <300 <20/400 -, +, ++

° ARC = anterior radius of curvature (3 mm zone), * PRC = posterior radius of curvature (3 mm zone),

† Pachy = Thinnest pachy (µm), °° BDVA = best corrected distance visual acuity

Treatment options for keratoconus include glasses in early disease and a variety of contact

lenses (CL) in several stages of keratoconus (rigid gas-permeable lenses (RGP), Rose K, hybrid

lenses, scleral lenses, etc.). Intrastromal corneal ring segments (ICRS) can be implanted to

reduce the corneal curvature in patients who lack functional vision with glasses or contact

4

lenses. When the above treatment options fail to offer adequate visual acuity, i.e. in advanced

keratoconus, corneal transplantation can be considered. Even though there is no definite cure

for keratoconus, a method to stabilize disease progression is available since the early 2000s:

corneal cross-linking (CXL). In this treatment riboflavin and ultraviolet A light are used to

produce a photochemical reaction, resulting in an increase of corneal rigidity. Cross-linking has

significantly altered the care for keratoconus patients.(12)

Prior to the cross-linking era, there was little incentive for early keratoconus diagnosis as there

were no means to arrest the natural course of the disease other than advising patients against

eye rubbing. Ideally, timely cross-linking would prevent progression from a mild to moderate

or severe stage and thus allow for a reduction in lifelong contact lens dependency as well as

further progression towards a corneal graft.

1.b. Purpose

This paper aims to research whether screening for keratoconus is worthwhile, based on the

current evidence for early detection and treatment of keratoconus, and if so, which screening

strategy could be implemented. By means of the World Health Organization (WHO) principles

of screening, we will investigate whether early detection and treatment would result in reducing

morbidity and costs. We will address critical areas where knowledge remains insufficient.

5

2. Methods

A systematic search according to Preferred Reporting Items for Systematic reviews and Meta-

Analyses (PRISMA) guidelines was performed, selecting studies on the topics of natural history

of keratoconus, epidemiology, quality of life, cost of treatment, cost-effectiveness and cost of

illness (Pubmed search: keratoconus AND (screening OR cost OR cost-effectiveness OR

epidemiology OR natural course OR quality of life). Articles describing the mere diagnosis in

refractive surgery candidates were excluded by adaptation of advanced search details. Studies

were recovered from the Pubmed, Cochrane and Web of Science databases. All English

language abstracts were evaluated for inclusion in this review, without limitation on publication

date. The full PubMed search strategy and PRISMA flowchart can be found in Addendum 1.

Articles pertaining to the epidemiology of keratoconus, cost of illness, disease burden,

screening strategies and cost-effectiveness of screening and treatment were identified. All

articles were screened at title and abstract level.

The scientific quality of the remaining articles was assessed using the relevant Critical

Appraisal Tool (CAT) issued by the Joanna Briggs Institute (JBI).(13-16) An example can be

found in Addendum 2. Relevant references in the selected articles were additionally included

and went through the same selection process. In total, 187 articles were included in the

qualitative synthesis concerning keratoconus.

Next to this systematic search, articles discussing school-based vision screening were searched

in PubMed. Articles that were found to be relevant to the discussion sections in this paper were

manually selected.

6

3. Results

The classical screening criteria defined by Wilson and Jungner for the WHO in their 1968

statement ‘Principles and practice of screening for disease’ (Table 2) will be used as a

guideline. (17)

Table 2: Wilson and Jungner screening criteria

1 The condition sought should be an important health problem.

2 There should be an accepted treatment for patients with recognized disease.

3 Facilities for diagnosis and treatment should be available.

4 There should be a recognizable latent or early symptomatic stage.

5 There should be a suitable test or examination.

6 The test should be acceptable to the population.

7 The natural history of the condition, including development from latent to declared

disease, should be adequately understood.

8 There should be an agreed policy on whom to treat as patients.

9 The cost of case-finding (including diagnosis and treatment of patients diagnosed)

should be economically balanced in relation to possible expenditure on medical care as

a whole.

10 Case-finding should be a continuing process and not a “once and for all” project.

The original order of the above criteria will be adapted to create a logical and readable text

structure. For the sake of clarity, results and discussion for every screening criterion will be

discussed together.

3.a. The condition sought should be an important health problem

The importance of a health problem can be regarded from the point of view of both the

individual and the community. It can be appraised in two ways: either by its degree of

prevalence, or by the impact on quality of life of the individual.

3.a.1. Prevalence and incidence

Prevalence is calculated as the number of affected individuals at a given time divided by the

number of individuals in the population, thus calculating the expected number of patients with

a certain disease in the population. Incidence on the other hand, refers to new - rather than

existing – cases that occur in the population over a specified period of time.(18)

7

Keratoconus has long been considered an uncommon disease based on the prevalence rate of

54.5 per 100,000 published by Kennedy et al in 1986.(19) A recent epidemiologic study in the

Netherlands showed that the annual incidence and prevalence of keratoconus are five- to tenfold

higher than previously reported. The annual incidence in white patients aged 10-40 was 1 in

7,500, while the prevalence in the general population was estimated to be 1 in 375.(20)

Findings of epidemiologic studies are listed in table 3A and 3B. The differences in

denominators, study design (retrospective/prospective) and diagnostics (keratoscopy or corneal

topography) hinder direct comparison of reported data from various regions. Advances in

corneal imaging are presumably responsible for the increase in reported prevalence.

Table 3A: Retrospective/prospective studies

Country Year Duration

(years)

Diagnostics Incidence per

100,000

Prevalence

per 100,000

USA(19) 1986 48 Irregular retinoscopic reflexes and

irregular mires on keratometry

2 54.5

Finland(21) 1986 20 Hospital registration of diagnosis 1.5 28.8

UK(22) 2000 10 Hospital registration of diagnosis

(age 10-44 y)

19.6 (Asians)°

4.5 (whites)°

229 (Asians)

57 (whites)

UK(23) 2004 6 Hospital registration of diagnosis 25 (Asians)

3.33 (whites)

NS

Saudi Arabia(24) 2005 1 Prospective registration of

diagnosis (Irregular retinoscopic

reflexes and irregular mires on

keratometry)

20 NS

UK(25) 2005 4 Videokeratography 32.3 (Asians),

3.5 (whites)

NS

Denmark(26) 2007 11 Hospital registration of diagnosis 1.3 86

USA(27) 2009 4 Medicare expences, age > 65 y NS 15.7-18.3

Iran(28) 2012 1 Clinical signs and Tomey TMS-4 22.3 NS

Lebanon(29) 2016 5 Hospital registration of diagnosis 530 (<14 y),

3,780 (>14 y)

NS

Netherlands(20) 2017 4 Registration of diagnosis for

reimbursement

13.3* 265

° age-specific (10-44 years)/* age-specific (10-40 years), NS: not specified

8

Table 3B: Screening studies

Country Diagnostics Sample size Prevalence in cohort

New

Zealand(30)

Medmont corneal topographer 441 secondary school

students (age 13-18)

680 per 100,000

Iran(31) Pentacam (Holladay criteria) 4,592 (age 40-64 y) 760 per 100,000

Iran(32) Slit-lamp, Pentacam HR 2,703 (age > 10 y) 3,590 per 100,000

Iran(33) Slit-lamp, Tomey TMS-4,

Orbscan II

1,027 medical students 2,500 per 100,000

Israel(34) Videokeratography 987 college students 2,340 per 100,000

Saudi

Arabia(35)

Pentacam HR 522 patients (age 6-21 y) 4,790 per 100,000

India(36) Mean SE ≥ 48D with non-

automatic keratometer (no

topographer available)

5,711 (age >30 y) 2,300 per 100,000

3.a.2. Quality of life

In healthcare economics, the concept of quality-adjusted life years (QALY) has been developed

as a common impact measure of the burden of disease on both the quantity and quality of life.

It takes into account the impact of a treatment on a patient's length of life, as well as the impact

on their health-related quality of life. One QALY signifies one year in perfect health. The

different health states individuals experience over time, are weighted according to the utility

scores associated with them. These utility scores are the value that is attached to a certain health

state, measured in terms of preference (desirability).(37, 38)

The National Eye Institute-Vision Function Questionnaire (NEI-VFQ-25) is a commonly used

tool to asses vision-related quality of life: it measures different subscales and dimensions of

self-reported vision targeted health status - such as general, near, distance and color vision, as

well as dependency, social function and mental health.(39) The questionnaire has been

validated in different studies, and is proven to be sensitive to the influence of several

ophthalmologic diseases (e.g. age-related macular degeneration (ARMD), diabetic retinopathy

(DRP), glaucomatous field loss, etc.).(40)

Keratoconus patients have significantly impaired vision-related quality of life similar to those

with severe ARMD, to an extent disproportionate to visual acuity (VA) measures.(3, 41) They

tend to score lower on all subscales of NEI-VFQ-25 compared to a control group of contact

lens (CL) wearers, with significant lower scores in the subscales of general vision, ocular pain,

9

near vision, vision-specific mental health, vision-specific role difficulties, and peripheral

vision.(40) Binocular entrance VA worse than 20/40 was associated with lower quality of life

scores on all scales except general health and ocular pain in the Collaborative Longitudinal

Evaluation of Keratoconus (CLEK) cohort. A steep keratometric reading (average of both eyes)

>52 diopters (D) was associated with lower scores on the mental health, role difficulty, driving,

dependency, and ocular pain scales.(3) Visual impairment (defined as entrance high contrast

visual acuity <20/40 but >20/200) due to keratoconus in the baseline findings of the CLEK-

study is 8.5% of all participants.(42) Even patients without visual decline show significantly

lower vision-associated QoL as compared to a control group of CL wearers.(43) The impact on

QoL also worsens with time.(41)

Health utility calculations based on the CLEK cohort have shown a significant association

between reported health utility (based on SF-6D questionnaire) and best-corrected visual acuity

(BCVA) of the better eye.(44) A recent study by Sahebjada et al. confirmed this finding.(45)

Changes in the QoL scales are associated with changes in the asymmetry of VA and corneal

curvature, yet with less impact than changes in the better eye.(46) This is a good reminder for

clinicians not to ignore the better eye, as the clinical focus is often directed towards the worse

eye. Whether the need for specialty CL in order to achieve adequate binocular vision (with

poorer unaided vision) significantly influences QoL, remains unknown.

3.a.3. Discussion

The question can be asked which criteria should be used to qualify a disease as an important

health problem. Does this mainly refer to a high prevalence, or should the impact on quality of

life be regarded? Or rather, should we focus on economic implications of the disease?

The original paper by Wilson and Jungner outlining the principles of screening, states the

following: “To be considered an important problem, a disease need not necessarily have a high

degree of prevalence, though that would be a usual requirement. […] Clearly the importance

of the problem needs to be considered from the point of view both of the individual and of the

community. Thus conditions with serious consequences to the individual and his or her family

in general may warrant relatively uneconomic screening measures; while certain individually

mild conditions, but having serious consequences for the community if not discovered early and

treated, will justify screening on these grounds.”(17)

Despite the relatively low prevalence of keratoconus, the public health impact should not be

underestimated as it affects young and economically active patients with a considerable effect

on quality of life. Because clinical examination of people with keratoconus typically reveals

10

normal best-corrected VA as well as modest ocular comorbidity, the common clinical idea is to

assume keratoconus to be a disease of modest consequence to its patient. However, considering

the above results of self-reported impact on the QoL, keractoconus is highly significant from a

patient’s perspective, and QoL-scores worsen with time.(41)

As such, we can conclude that the existing evidence suggests that the magnitude of the public

health impact of keratoconus is disproportionate to its prevalence and clinical severity. The

impact on public health is greater than it may appear to be prima facie.(3) Nevertheless, most

of this evidence is based on findings of the CLEK-study, which dates back to the era before

cross-linking, and before the newer generation of contact lenses. All in all, little up-to-date

evidence is available concerning the quality of life of keratoconus patients.

3.b. The natural history of the condition, including development from latent to

declared disease, should be adequately understood

3.b.1. Demographics and natural progression

The mean age at the time of keratoconus diagnosis varies between different reports, but is most

commonly in early adulthood and continues into earning and child-rearing years. This means

mainly economically active patients are affected.(47) In younger patients with untreated

keratoconus, the risk of progression (defined as an increase in Kmax) is significantly higher:

those younger than 17 years old are likely to have more than 1.5 D of Kmax progression over

a 12-month period.(48)

Higher rates of keratoconus are reported in the Middle East and Asia, but these data mainly

originate from screening studies and no similar prospective studies have been performed in

Caucasians. An ethnic variability may however exist, based on findings of increased relative

risk in Asians compared to Caucasians in 2 UK-based retrospective reports.(22, 23) Black and

Latino persons are reported to have approximately 50% higher odds of having keratoconus

compared to white persons.(49) The higher prevalence rates in the Middle East from mainly

Muslim communities may be correlated with the increased likelihood of consanguinity, which

is shown to be a risk factor for keratoconus.(50) Moreover, untreated Middle-Eastern patients

demonstrated significantly more progression (i.e. greater Kmax increase) than Europeans and

East Asians in a recent meta-analysis by Ferdi et al.(48)

Large-scale longitudinal observational studies have documented the natural course of

keratoconus in the pre-crosslinking era (cfr. Table 4). Keratoconus either self-limits at some

point, presumably due to natural cross-linking, or evolves towards progressive corneal thinning

11

with apical scarring and risk of hydrops, requiring penetrating keratoplasty (PK). During the 8

years of follow-up, CLEK patients exhibited a gradual decrease in high- and low- contrast

BCVA.(51) The study’s five-year incidence of corneal scarring was 14% overall. Progression

of disease in terms of changes in corneal curvature and VA resulted in continued decline in

vision-related QoL as measured by the NEI-VFQ.(51) The Dundee University Scottish

Keratoconus Study (DUSKS), a prospective observational longitudinal study, similarly

followed 200 keratoconus subjects for 4 years. They also found a decrease in unaided vision

(14%) and recorded best spectacle-corrected visual acuity (BSCVA) (24%) by one or more

lines. During the study period, 4.5% of keratoconic eyes progressed to surgery.(52)

A steeper Kmax at the time of diagnosis (certainly patients with greater than 55 D Kmax) is

significantly associated with more progression.(48)

Table 4: CLEK vs DUSKS (Adapted from Weed et al.)(53)

CLEK (16 clinics, n=1209) DUSKS (n=200)

Age (years): enrolled

diagnosed

39.3+-10.9

27.3+-9.5

30.9+-10.4

24.05+-8.97

Male (%) 55.9 62.5

Family history (%) 13.5 5

Race (%) African-American 19.9

White 68.5

Other 11.6

Asian 6.5

White 93

Afro-Caribbean 0.5

Eye rubbing (%) 50.5 48

Vogt striae (%) 45.5 (1) 67 (2) 68

Fleischer ring (%) 74.6 (1) 86 (2) 89

Scarring (%) 36.6 (1) 21 (2) 20

Corneal thickness (µm) N/A (1) 443 (2) 412

Contact lens (%) 73 (1) 80 (2) 76

Binocular VA (%) 77.9 6/12 (1) 93 6/9 (2) 90

Steep K (D) 50.8+-5.4 (1) 51.74+-5.36

(2) 50.76+-4.86

Flat K (D) 47.9+-5.4 (1) 46.66+-4.55

(2) 45.74+-4.09

Penetrating keratoplasty (%) 9.8 (1) 10.5 (2) 15

Atopy (%) 53 41.5

(1) and (2): review moments in DUSKS (spanning a 4 year-period)

12

3.b.2. Risk factors

Next to ethnicity, eye rubbing and a positive family history, multiple significant risk factors for

keratoconus have been identified. Table 5 lists the evidence as found in the included articles.

Table 5: Significant risk factors for keratoconus

Risk factor Result Author, year published

Allergy Odds ratio (OR) 4.22

OR 2.09

Gordon-Shaag et al., 2013(50)

Naderan et al., 2015(54)

Asthma OR 2.00

OR 3.92

OR 1.31

Merdler et al., 2015(55)


Woodward et al., 2016(49)

AC/CB/VKC° OR 6.00 Merdler et al., 2015(55)

Consanguinity OR 3.96 for 1st cousin and 2nd cousin

Higher mean inbreeding coefficient in KC


Jamali et al., 2018(56)

Diabetes Higher prevalence of DM type 2 in KC

No difference in prevalence of DM in KC

patients vs control; having DM decreases odds

of severe KC

Protective effect of DM type 2 against KC

Lower odds of KC (uncomplicated DM: OR

0.80, complicated DM: OR 0.48)

Kosker et al., 2014(57)

Kuo et al., 2006(58)


Seiler et al., 2000(60)


Down syndrome OR 6.22 Woodward et al., 2016(49)

Education OR 4.79 (education >12 y)

Higher risk in lower education



Eye rubbing OR 10.15

OR 3.37

OR 6.80

OR 4.33



Jamali et al., 2018(56)


Family history of

KC

OR 9.68

OR 8.40



Parents’ education OR 0.35 (fathers education) Gordon-Shaag et al., 2015(61)

OSA† Higher risk for OSA in KC

Higher risk for OSA in KC (10-20 times

higher than general population)

OR 1.13


Pedrotti et al., 2018(63)


VKC* OR 8.67 Naderan et al., 2015(54)

° AC/CB/VKC = combination of allergic conjunctivitis, chronic blepharitis, and vernal

keratoconjunctivitis, † Obstructive Sleep Apnea, * Vernal Keratoconjunctivitis

13

Variations in odds ratios and statistical significance can be explained by differences in study

design and number of patients examined, as well as by differences in population characteristics.

3.b.3. Development from latent to declared disease

A consensus paper regarding keratoconus definitions, diagnosis and management was

published in 2015, based on expert panel discussions using the Delphi method. In this paper, it

is proposed that keratoconus can be diagnosed when the following findings are present:

(a) abnormal posterior ectasia, (b) abnormal corneal thickness distribution, and (c) clinical

noninflammatory corneal thinning. It is stated that exact values for any parameter will vary

based on the machine being used and, for elevation values, the reference surface. Consensus

was that tomography (e.g., Scheimpflug or optical coherence tomography) is currently the best

and most widely available test to diagnose early keratoconus, and that posterior corneal

elevation abnormalities must be present to diagnose mild or subclinical keratoconus.(5)

Progression of keratoconus is defined by a consistent change in at least 2 of the following

parameters (and the magnitude of the change has to be above the normal noise of the testing

system): (a) steepening of the anterior corneal surface, (b) steepening of the posterior corneal

surface, and/or (c) thinning and/or an increase in the rate of corneal thickness change from the

periphery to the thinnest point.(5) There is no consensus on more specific or quantitative data

regarding diagnosis nor progression.

A recent meta-analysis by Ferdi et al. investigated the evolution and natural progression of

untreated keratoconus. A significant increase in Kmax of 0.7 D at 12 months was demonstrated.

Younger patients, patients with steeper Kmax at presentation, and Middle-eastern patients

experienced more progression. No significant changes in visual acuity, refraction, or thinnest

pachymetry were demonstrated. Although these last 3 parameters are undoubtedly important

aspects of keratoconus progression, they may be less sensitive measures of progression

compared to topography. In order to tailor progression predictions to individual patients, more

data providing quantitative evidence of progression are needed.(48)

3.b.4. Discussion

The natural history of keratoconus is poorly understood because of lack of sufficient data.

Nonetheless, this information is fundamental in making informed decisions on whether

interventions - aiming to stabilize progression - have an advantageous benefit-risk-ratio.

To our knowledge, no formal definition for a latent stage of keratoconus, nor specific

quantitative data concerning keratoconus progression from latent to declared disease are

14

available in literature. The natural course of keratoconus can be seen as a progressive

continuum, in which it is difficult to identify a set point where it progresses from latent to

declared disease.

Dependency on specialty contact lenses, a significant loss of visual acuity, acute hydrops, or

the need for keratoplasty can be regarded as hard endpoints. As such, we could conclude that

the diagnosis of keratoconus can be seen as the goal of screening, aiming to reduce the incidence

of the above-mentioned hard endpoints.

3.c. There should be a recognizable latent or early symptomatic stage

The diagnosis of keratoconus can be seen as the goal of screening, whereas the early

symptomatic stage might already be the moment when cross-linking is indicated (cfr. infra).

Patients should thus be identified at an earlier, possibly pre-symptomatic, point in time.

Advanced keratoconus stages show typical topographic patterns that are easy to recognize;

however, the detection of the earliest, subclinical stage can be challenging. This is of particular

importance in patients requesting refractive surgery (e.g. laser in situ keratomileusis (LASIK)),

since subclinical KC in these patients could lead to iatrogenic keratectasia when

undiagnosed.(64)

Various topographic metrics and indices to detect subclinical and definite keratoconus have

been published. Tomographic systems add significantly more information, e.g. due to greater

corneal coverage and by analyzing the posterior corneal surface.(65) Most published indices

are based on a combination of keratometry and central corneal thickness (CCT) values.

Jafarinasab et al. demonstrated that anterior and posterior corneal elevation data obtained by

Orbscan II can discriminate between keratoconus and normal corneas, but that the reliability of

their indices is lower in differentiating subclinical KC from normal cases.(66) Discriminant

function values obtained from corneal Zernike coefficients from corneal anterior and posterior

surfaces and from spatial-thickness profile data, have proven to detect subclinical keratoconus

with reasonable accuracy.(64) Belin/Ambrosio enhanced ectasia total derivation value (BAD-

D) as displayed by Pentacam was found to be a strong parameter to differentiate both

keratoconus and subclinical keratoconus from normal corneas.(67) Hashemi et al. identified

BAD-D, the index of vertical asymmetry (IVA), the index of surface variance (ISV), and 5th

order vertical coma aberration as the best diagnostic criteria for the diagnosis of subclinical

keratoconus with a sensitivity of 83.6% and specificity of 96.9% using Pentacam HR.(9)

Unfortunately, no single descriptor has 100% sensitivity and specificity, indicating that

topographic/tomographic indices should always be interpreted alongside other clinical data.

15

Efforts are being made to develop machine learning methods (artificial intelligence) for

detecting keratoconus.(64, 68)

3.d. There should be a suitable test or examination

Even though definitions differ in terms of nomenclature, corneal topography is a sensitive tool

in detecting keratoconus- or keratoconus suspect patients.(8, 10, 67, 69, 70)

Other examination options include corneal biomechanical measurement devices (e.g. Ocular

Response Analyser, Reichert Ophthalmic Instruments, NY, USA), anterior segment OCT(71),

scissoring reflex on retinoscopy(72), or even smartphone-based devices(73); however, these

require clinical validation.

3.e. The test should be acceptable to the population

Corneal imaging devices are a non-invasive, painless, safe and simple imaging method and are

generally easily accessible to opticians and local hospitals in developed countries. Corneal

imaging also allows detection of subclinical keratoconus, which is of vital importance in

screening refractive surgery candidates.(74)

3.f. There should be an agreed policy on whom to treat as patients

Disease progression, and the consequent deterioration of uncorrected visual acuity (UCVA) and

BCVA, defines the need for treatment. As mentioned above, steepening of the anterior and/or

posterior corneal surface, and/or thinning and/or an increase in the rate of corneal thickness

change from the periphery to the thinnest point have been identified as criteria for keratoconus

progression.(5) However, no consensus is reached on specific, quantitative criteria.

As a consequence, different studies describe their own parameters for progression (non-

exhaustive list):

- A ten-letter loss of BCVA and a 3 D increase in corneal curvature, since these are

associated with a significantly larger decline in QoL and should be avoided.(48)

- Any of the following criteria for a period of 24 months: (a) an increase of ≥ 1.0 D in the

steepest keratometry measurement, (b) an increase of ≥ 1.0 D in manifest cylinder, or

(c) an increase of ≥ 0.5 D in manifest refraction spherical equivalent.(43)

- Deterioration of ≥ 1 line in BCVA, increase of ≥ 1.0 D in refractive error, and

topographically as an increase of ≥ 1.0 D in maximum keratometric reading (Kmax) on

serial corneal topographs within the last 6 months.(75)

16

- Any of the following criteria over a period of 6 months: an increase in mean K or steep

K (K2) of ≥ 0.75 D, an increase in cylinder of ≥ 1.0 D, an increase in sphere of ≥ 1.0 D,

and a decrease of 2 lines of CDVA.(76)

- Any of the following criteria over a period of 12 months: increased simulated maximum

keratometry (sim max K) of ≥ 1.0 D based on corneal topography, or ≥ 1.0 D increase

in the curvature of the steep meridian based on keratometer measurements, or increased

cylinder of ≥ 1.0 D based on the manifest refraction, or loss of ≥ 2 lines of BSCVA

attributable solely to the progression of KC.(77)

These varying criteria for keratoconus progression demonstrate that the decision on whether or

not to proceed with treatment to stabilize the disease, is often left to the discretion of the

surgeon. In this decision process, important parameters associated with increased risk of

topographic progression – such as young age, and steeper Kmax at presentation – should be

taken into account. For these patients with higher risk, closer follow-up and a lower threshold

for treatment should be minded.(48)

3.g. There should be an accepted treatment for patients with keratoconus

Historically, only glasses and lenses were available for refractive correction in keratoconus;

progression to hydrops or corneal scarring could not be avoided, and could only be managed

by keratoplasty. In the last decades, there has been a paradigm shift in the treatment of

keratoconus due to the introduction of cross-linking, which has shown to slow or halt

progression (cfr. infra). The treatment of choice for a particular patient depends on the stage of

disease, and whether or not progression is documented.

3.g.1. Treatment options to improve visual acuity

a. Optical correction: glasses and contact lenses

Patients with very mild or early keratoconus can achieve adequate vision with glasses or soft

contact lenses in the vast majority. Mild to moderate keratoconus, with higher degrees of

(irregular) astigmatism can be treated with rigid gas permeable (RGP) or hybrid contact lenses,

which create a new refractive surface in front of the conical cornea. The space between the

corneal surface and rigid contact lens is filled with tears, thus masking the underlying irregular

shape. Scleral lenses function likewise, but rest on the conjunctiva and vault over both the

cornea and limbus, thus creating a more stable and better-centered fit. These are generally used

for moderate to advanced keratoconus, decentered cones, or patients suffering from dry eye

disease.(78, 79) Recent developments in lens material and design, such as hybrid or specialty

soft contact lenses, allow for a combination of longer wearing time, more patient comfort, and

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good visual performance.(12) The use of scleral lenses has even shown to reduce the need for

corneal transplants in severe keratoconus (Kmax ≥ 70D).(79)

b. Intrastromal corneal ring segments (ICRS)

Intracorneal ring segments (e.g. Intacs (Addition Technologies, USA)) were originally designed

for myopia correction. These are 0.25 - 0.35 mm thick segments made from inert material and

are implanted in the corneal stroma. The ring segments should embrace the steepest keratoconus

meridian, thus pursuing maximal flattening of the conus.

The best candidates for ICRS are patients with mild to moderate keratoconus, low spherical

equivalent and average keratometry readings of less than 53 D. Several studies show significant

improvement in uncorrected visual acuity (UCVA), BSCVA, spherical equivalent, and a

reduction of keratometry.(80, 81) However, study samples and duration of follow-up are

limited, and several articles describe regression at longer follow-up periods, suggesting that

implantation of ICRS does not significantly influence progressive keratoconus in patients with

confirmed progression of the disease.(76, 82) Moreover, it should be noted that complication

rates are high (up to 40%; with ring exposure secondary to corneal thinning over the implants

as a major concern)(81), and that long-term results are unpredictable.(76, 82)

c. Keratoplasty

c.1. Penetrating keratoplasty (PK)

Historically, PK was the only treatment option available in the management of severe

keratoconus. This technique involves replacing full-thickness corneal tissue of the patient

(including healthy endothelium) with a donor cornea. The mean time to corneal grafting from

diagnosis varies between reports, ranging from 3.2 to 8.8 years. However, these data refer to

the time before the availability of CXL or the latest generation of specialty contact lenses. The

time to grafting will presumably be longer now.(48)

Disadvantages of PK are that it is an ‘open-sky’ procedure, that there is a prolonged course of

surgical wound healing necessitating tight suturing, the risk of suture-related infections and the

persistent risk of wound dehiscence.(83) Long-term outcomes of PK in keratoconus show a

relatively high risk of rejection (up to 48% at 20 years follow-up), as well as a risk of graft

failure, and recurrence of keratoconus.(84) Notwithstanding these disadvantages, PK is still a

frequently used and effective technique in the care for patients with advanced keratoconus.(83,

85, 86)

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c. 2. Deep anterior lamellar keratoplasty (DALK)

Contrary to PK, DALK involves replacing the affected stroma with donor corneal tissue, in

which the recipient retains his own endothelium. The advantages of DALK over PK include a

lower prevalence of allograft rejection and faster visual rehabilitation. Due to these advantages,

the relative contribution of lamellar techniques is increasing.(83, 86) Nevertheless,

postoperative astigmatism, steroid induced ocular hypertension and persistent epithelial defects

are reported in both DALK and PK with similar frequency. Complications during the DALK-

procedure can necessitate a conversion to PK.(87)

A Cochrane review comparing outcomes of PK and DALK in keratoconus concluded that both

techniques are successful in improving BCVA, SE and keratometric astigmatism at 12 months

postoperatively. However, there was insufficient evidence to support a difference in outcomes

with regards to BCVA at any of the time points analyzed, or that there is a difference in

outcomes with regards to graft survival, final UCVA or keratometric outcomes. More

randomized controlled trials are required to further assess which type of keratoplasty is

preferable in treating keratoconus.(87) Henein et al. concluded in a systematic review that

DALK is associated with better refractive astigmatism and reduced rejection episodes, yet

visual outcomes are better with PK. There was no difference in SE and keratometric

astigmatism.(88)

3.g.2. Treatment option to stabilize progression: Corneal cross-linking (CXL)

a. The procedure

Corneal cross-linking intends to strengthen the corneal stroma and stabilize its form. This is

done by exposing corneal tissue treated with the photosensitizing riboflavin (vitamin B2) to

370nm ultraviolet light (UVA). The chemical reaction which is hence produced (e.g. production

of free radicals) forms chemical bonds between collagen fibrils, thus strengthening the

tissue.(89) It is only performed in patients with adequate visual potential, absence of corneal

scarring, and central corneal thickness (CCT) of at least 400µm (to avoid irradiation damage to

the corneal endothelium).(75) In more advanced stages of keratoconus, stromal thinning often

leads to CCT of less than 400 micron, thus limiting the applicability of CXL in this group of

patients.

Two established methods can be used: the transepithelial or the epithelium-off technique. Both

can be performed as outpatient procedures under topical anesthesia. The transepithelial

technique is performed by directly instilling a 0.1% riboflavin solution for a minimum of 16

19

drops over 30 minutes, after which irradiation with UVA (370 nm wavelength, irradiance of 3

mW/cm 2) is started. This second phase also lasts approximately 30 minutes, while 1 drop of

riboflavin is continuously instilled every 5 minutes.(89, 90) Different methods have been

developed to enhance the permeability of riboflavin, a hydrophilic molecule, through the

hydrophobic corneal epithelium: the use of benzalkonium chloride, EDTA, gentamicin,

iontophoresis, as well as minimal trauma (through epithelial poke marks) to the epithelium.(91)

The epithelium-off technique consists of the same treatment protocol, preceded by abrasion of

the corneal epithelium to facilitate penetration of riboflavin. Before the application of UV light,

CCT is measured, and if less than 400 µm, hypotonic riboflavin can be applied until CCT is ≥

400 µm.(75) A pressure patch is usually applied postoperatively. Both procedures are followed

by postoperative topical antibiotics and anti-inflammatory drops.(89, 90)

b. Evidence for efficacy

Corneal cross-linking has been widely available for more than a decade and has demonstrated

its efficacy in halting further progression and safety in numerous randomized controlled

trials.(75, 89, 90, 92) Craig et al. published a meta-analysis of studies on epithelium-off cross-

linking for the management of keratoconus and secondary ectasia in 2014. Statistically

significant improvements were found in visual acuity, topography, refraction and astigmatism,

and central corneal thickness at 12 month follow-up compared to baseline pre-procedure values.

However, the authors noted that few well-conducted randomized controlled clinical trials

(RCT) with long follow-up are available.(90) This concern was shared by the Cochrane

reviewers, who concluded that evidence for the use of CXL in the treatment of keratoconus was

limited due to the lack of properly conducted randomized clinical trials.(89)

More recent studies support the evidence that CXL is effective in improving the maximum

keratometry value, BDVA, and UCVA in eyes with progressive keratoconus, and that it

achieves long-term stabilization of the ectasia.(75, 92, 93) There are a few trials with longer-

term follow-up (up to 10 years) indicating treatment success in the majority of patients; with

reported stability after 10 years of follow-up in nearly 80% of the patients.(93, 94)

c. When to treat

General perception is that documentation of disease progression is warranted to perform cross-

linking, but there is no international consensus on what exactly constitutes as documented

progression. We are also unable to reliably predict the future rate of progression in early disease.

20

Treatment at the pre-symptomatic stage of disease without any documented progression would

inevitably result in overtreatment; yet later stages of keratoconus often show significant corneal

thinning, while a minimum CCT of 400µm is advised for CXL.

Treatment of patients at an early stage renders safety of the procedure of vital importance.

Epithelium-off CXL is associated with a number of possible complications. Transient corneal

haze occurs in virtually all eyes and resolves with time. Serious complications such as infections

(0-3%), stromal scarring (0-6%) or sterile infiltrates (2-4%) have been reported in varying

proportions, yet can be regarded as uncommon.(90, 91) Even though transepithelial CXL lacks

many of the complications of epithelium-off CXL, the latter appears to be more efficient in

stabilizing Kmax.(91)

We can thus summarize that multiple studies show the effectiveness of CXL in halting or

slowing progression of keratoconus, and that it is a safe treatment. Whether or not re-treatment

will be necessary in the long term (after 20 or 30 years) remains to be investigated.

d. Combined treatment

Cross-linking can be performed as a single procedure, or can be combined with refractive

surgery (e.g. photorefractive keratectomy (PRK), LASIK, or ICRS) in order to improve visual

acuity, known as ‘CXL plus’.(95, 96)

A review by Hashemi et al. showed that combined same-day ICRS and CXL might have an

added value over each technique separately. The qualitative analysis of data from 17 trials

showed that simultaneous surgery patients performed significantly better in terms of spherical

refractive errors and flat-K compared to CXL-first, and significantly better in terms of steep-K

compared to each technique separately. Uncorrected and best-corrected visual acuity did not

show statistically significant differences between groups. The authors mention limitations

concerning small sample size, short-term follow-up, a lack of high-quality study protocols and

well reported outcomes.(95)

Labiris et al. performed a prospective, controlled trial comparing quality of life between a group

of patients with keratoconus stage 1 (Amsler-Krumeich classification) and BSCVA of 20/20 in

both eyes, who underwent either CXL or CXL combined with topography-guided PRK (t-PRK)

(tCXL). The group that underwent CXL presented a significant improvement in the dependency

subscale 1 year post-operatively; whereas tCXL group presented a significant improvement in

the near activities, role limitations, dependency, and driving subscale scores.(43) At the three-

year follow-up time point, additional significant improvement was detected in the driving

21

subscale in the CXL group, and in the distant activities in the tCXL group. These results indicate

that even early CXL in patients with good BSCVA has a beneficial impact on self-reported

QoL, and that CXL or tCXL should be delivered as soon as progression is established - even at

the very early stages of the KC disease continuum.(97)

e. Cost-effectiveness of CXL

A Canadian cost-utility analysis based on simulated cohorts compared total costs and Quality-

Adjusted Life Years (QALYs) of early cross-linking with conventional PK. In this study all

relevant medical costs were assessed, but broader economic impact was not incorporated in the

study design (e.g. absence from work due to consultations or surgery, driving ability etc.).

Despite conservative assumptions, Leung et al. found that CXL is cost-effective compared with

conventional PK at an Incremental Cost-Effectiveness Ratio (ICER) of Can$9,090/QALY (i.e.

approx. €6,060/QALY). This is well below cited thresholds of Can$20,000 – 100,000/QALY

for cost-effective interventions in Canada, or US$50,000/QALY as proposed in the United

States.(98) Godefrooij et al. similarly used a Markov-model to calculate cost-effectiveness of

CXL from a healthcare perspective (thus not taking into account costs incurred outside of the

healthcare system). They found an ICER of €54,384 per QALY gained ($59,822/QALY),

assuming a stabilizing effect of CXL of 10 years; decreasing to €10,149/QALY

($11,163/QALY) assuming a lifelong stabilizing effect of CXL.(99) A Markov-model

developed by Salmon et al. showed that CXL is cost effective compared with standard

management at an incremental cost of £3,174 per QALY (€3,629/QALY, or US$4,086/QALYa)

over a 25-year time horizon. If CXL can only provide a one-off benefit of 5 years of halted

progression, this value may rise to over £33,263 per QALY (€38,360/QALY, or

US$43,192/QALYb).(100) The differences in the ICERs mentioned by the last two articles, can

be explained by the different data used to base assumptions on regarding disease progression,

as well as by the duration of the Markov model (25 years in the study by Salmon et al. versus

the duration of the life of each patient in the model by Godefrooij et al), and by the choice of

utility values (corneal curvature in the study by Salmon et al. versus VA in the model by

Godefrooij et al.).

3.g.3. Discussion

Different treatment strategies for optical correction, including RGP contact lenses(101, 102)

and ICRS(103) have proven to have a positive impact on the vision related quality of life.

a Currency converted via xe.com on 22th of April 2019 b Currency converted via xe.com on 22th of April 2019

22

Various studies support the positive impact of CXL on self-reported quality of life.(43, 97)

The CLEK-study showed significant improvements in quality of life scores after PK as well

(104); yet it remains impaired, despite satisfactory results on visual outcome measures.(40, 102)

In the Netherlands, significantly fewer corneal transplants were performed for treating

keratoconus following the introduction of cross-linking (reduction of 25% in the 3 years

following introduction of cross-linking as compared to the 3 years before the

introduction).(105) Sandvik et al. demonstrated a similar trend in Norway, where the frequency

of keratoplasty for keratoconus has been more than halved.(106) Alongside the introduction of

CXL, improvements in contact lens design might also partially explain the reduced need of

corneal transplants.(79) If this trend would continue in other countries in the future, this could

mean that costs and morbidity due to PK (e.g. rejection) would diminish.

In summary, different treatment options are available to improve visual acuity, while having a

positive impact on vision-related quality of life. However, corneal cross-linking is the only

treatment option available that has proven to stabilize progression, and leads to a reduction in

the need for more invasive corneal transplants. Even early CXL in patients with good BSCVA

has a beneficial impact on self-reported QoL; this emphasizes the need for early detection and

treatment of keratoconus.

3.h. Facilities for diagnosis and treatment should be available

Facilities for diagnosis and treatment are available in most developed countries. This can be

deducted from the places where clinical studies included in this systematic review took place.

The earlier we want to detect keratoconus in its progressive continuum, the more specialized

equipment is required for diagnosis and treatment. No specific data were found on the number

of topography/tomography devices per clinic or per country, nor on the access to cross-linking

or other treatment options.

Cataract surgical rate (CSR) and coverage (CSC) are used by the WHO as key indicators for

the delivery of eye care, and for monitoring progress towards universal eye health coverage in

different countries and regions. Strong associations are documented globally between CSR and

socioeconomic indicators, such as gross domestic product (GDP) per capita and human

development index (HDI). Countries with lower GDP per capita show a higher rate of cataract

blindness, lower CSC, and fewer patients with good vision outcomes.(107) Even though this

does not provide information on the care for keratoconus patients, it can be regarded as an

important indicator for the quality of and access to eye care in different regions.

23

Availability of diagnostic tools and treatments options for keratoconus in developing countries

may be restricted to larger hospitals, or is possibly not available at all. Consequently, patients

will likely be diagnosed in a later stage, with restricted access to contact lenses or surgical

options. If considering screening in these countries, it should presumably be organized in a

different way (e.g. by retinoscopy(72)). No articles were found covering these subjects.

3.i. The cost of case-finding (including diagnosis and treatment of patients

diagnosed) should be economically balanced in relation to possible expenditure

on medical care as a whole

Economic evaluations in healthcare can aid in allocating resources to prioritize these

interventions with maximum benefit at the lowest possible cost, since healthcare resources

remain scarce.(108) Costs of diagnosis and treatment can be assessed from either the societies’

point of view or the patients’ point of view, depending on patterns of reimbursement in different

countries.

3.i.a. Societies’ point of view

From a societies’ point of view, one needs to take into account both the medical and non-

medical costs. The unique epidemiology of keratoconus as a chronic eye disease affecting

young, economically active patients entails that keratoconus may result in productivity loss.

For instance, it is ‘good clinical practice’ to suspend rigid CL wear 3 weeks prior to corneal

imaging in order to reliably assess progression. Provided patients do comply with this demand,

it will inevitably impair their economic performances during this time. Other contact lens

related complications (such as lens overwear, infectious keratitis, loss of a lens etc.) may also

negatively impair the economic performance of this population. Saunier et al. examined 550

French keratoconus patients: in their case series almost 5% of participants reported having

changed their job because of keratoconus, 7.8% received keratoconus-related disability, and

12.5% reported having difficulties with activities of daily living and are considered

dependent.(109) To our knowledge, this aspect has not been assessed further in a keratoconus

population.

The only article included in this systematic review that estimates the lifetime economic burden

of keratoconus was published by Rebenitsch et al. They used a Markov-model to estimate the

lifetime cost of keratoconus care when compared with the lifetime cost of myopia. This was

estimated at $25,168, or equal to an annual cost of $653 per patient with keratoconus, over and

above the cost of routine vision care. Even though these estimations were made with a high

degree of uncertainty, this study shows that keratoconus represents a significant public health

24

concern.(47) However, as mentioned above, the non-medical costs (e.g. cost of productivity

loss) are not included in this estimation; which would mean the annual cost of $653 per patient

is an under-estimation.

Furthermore, health utilities – as used in cost effectiveness analyses – are typically based on

the VA of the better-seeing eye, irrespective of the type of optical correction needed to achieve

it. The impact of a patient’s dependence upon visual aids (particularly specialty CL) on the

quality of life in keratoconus patients remains to be investigated.

Lastly, we were unable to find studies that examine the cost-effectiveness of early detection

programs for keratoconus. As described above, arresting keratoconus by means of CXL has

proven to be cost-effective.(98-100) Whether a screening program would result in sufficient net

benefit for the population to justify the program, will likely be country-dependent.

3.i.b. Patients’ point of view

Multiple studies have shown an improvement in quality of life for keratoconus patients treated

with contact lenses or CXL (cfr. supra). From the patients’ point of view, the cost of diagnosis

and treatment, and whether these are reimbursed by public health systems or private insurance,

can be an important factor in the decision to proceed with treatment. In Brazil, for example,

CXL is available to all citizens or residents; hoping to prevent at least 90% of the keratoplasties

in keratoconus patients, and thus saving the Brazilian public health system over US$ 1,5 million

per year.(110) The total cost per cross-linking treatment in the Netherlands, including

preoperative assessment and follow-up during 1 year, was calculated by Godefrooij et al. at

€1,754.06 (± 177.23) or US$1,929.47 (± 194.95).(111)

In Belgium, CXL is not reimbursed by public health insurance to date. It would by all means

be unethical to screen for KC in order to halt progression by performing CXL early in the

disease continuum, without reimbursing this treatment.

3.i.c. Discussion

Due to insufficient economic data and studies, incorporating both medical and non-medical

costs in the care for keratoconus patients, it is not possible to calculate or estimate the cost-

effectiveness of (early) detection programs. Since cross-linking in itself is cost-effective, it

would be interesting to further research possible screening strategies. The cost of case-finding

will greatly vary depending on the screening strategy used (e.g. screening based on VA and

automated refraction versus topographic/tomographic screening). Countries that would

25

consider keratoconus screening programs in the future, should consider incorporating cross-

linking and other treatment options in their national public health insurance system.

3.j. Case-finding should be a continuing process and not a “once and for all”

project

Paediatric vision screening programs are well-established in most European countries, with

coverage up to > 95% in Austria, Czech Republic, Denmark, Finland, Flanders, Germany,

Hungary, Iceland, Luxembourg, the Netherlands, Norway, Serbia, Slovenia, Sweden, and parts

of the UK. Since these programs are designed to screen for and treat amblyopia, screening starts

early in life (first measurement from 3-7 years old).(112) Considering keratoconus manifests in

early adulthood, these programs could not be used as an existing framework to identify KC

patients.

Recent reports show an epidemic of myopia in East and Southeast Asia, with a prevalence of

myopia around 80-90% in children completing secondary schooling at the age of 17-18.(113)

A similar trend, though to a lesser extent, has been reported in Nordic European countries:

among 14‐ to 15‐year‐old school children in Finland, myopia doubled during the twentieth

century to about 21%.(114)

Ideally, vision screening at late adolescent age would target both uncorrected refractive errors

and allow detection of early keratoconus. Various screening strategies can be proposed: school-

based screening programs at the end of secondary school, screening of candidates undertaking

a driving test in order to obtain their driver’s license, screening of individuals with certain risk

factors (e.g. first-degree family members of KC patients, patients with VKC, patients with

connective tissue disorders), etc. The method of screening can vary as well: from visual acuity

testing or automated refraction, retinoscopy to look for a scissoring reflex, to topographic or

tomographic screening – possibly with smartphone applications or artificial intelligence to

reduce costs. Costs will also be determined by the person or organization carrying out the

screening examination (ophthalmologist, optometrist, nurse, etc.). A stepped approach - for

example by screening all adolescents at the end of secondary school with retinoscopy, and

referring those with a positive or suspicious scissoring reflex for topographic corneal imaging

– can be considered as well.(72)

Whether a certain screening program will be feasible, effective and cost-effective will be

determined by the above choices, and by the prevalence of keratoconus in that region.

26

To conclude, a quick and very simplified calculation considering keratoconus care in Belgium

provides some food for thought. There are 1,298,448 people between the ages of 15 - 25 in

Belgium (reference date: 01/01/2018).(115) Using the prevalence data published by Godefrooij

et al. (265 KC patients per 100,000 (20)), this would mean there are 3,441 KC patients in

Belgium between 15 and 25 years old. Assuming they could all be screened at the price of the

honorarium of corneal topography (€ 11.22, as stated by the Belgian national institute for health

insurance, RIZIV(116)), and that this would identify each and every one of them, it would cost

the Belgian public health care system €14,568,586. Using the cost of CXL as published by

Godefrooij et al. (€1,754.06 per patient, for the procedure and 1 year of follow-up), it would

cost € 6,035,720.46 to cross-link all Belgian keratoconus patients between 15 and 25 years old.

Adding the cost for screening, this sums up to €20,604,306. Even though this calculation is

oversimplified; it can provoke a useful discussion concerning the possibility of keratoconus

screening.

27

4. Final discussion

The principles of screening as defined by Wilson and Jungner can be applied to keratoconus

(screening), as elaborated in table 6.

Table 6: Wilson and Jungner screening criteria, applied to keratoconus

1 The magnitude of the public health impact of keratoconus is disproportionate to its

prevalence and clinical severity, and is greater than it may appear to be prima facie.

2 There is an accepted treatment for patients with recognized disease.

3 Facilities for diagnosis and treatment are available in developed countries, but may be

restricted in developing countries.

4 There is a recognizable subclinical and early symptomatic stage.

5 There is a suitable test or examination, namely topography or tomography.

6 Topography/tomography is a safe and non-invasive diagnostic tool.

7 The natural history of keratoconus is roughly known, yet sufficient and up-to-date details

on the evolution of disease are lacking.

8 Disease progression defines the need for treatment, but there is no consensus on specific,

quantitative criteria that define progression.

9 The cost of case-finding is currently unknown; however, it should be emphasized that

cross-linking in itself has been proven to be cost-effective.

10 No existing screening programs, nor research regarding such programs were identified

through this systematic review.

The introduction of corneal cross-linking has revolutionized the care for keratoconus patients,

since it is the first and only treatment that has proven to stop disease progression. Screening for

subclinical keratoconus - in order to treat these patients as soon as possible - could prevent

vision loss and associated loss of vision-related quality of life. This, in turn, could reduce

healthcare costs in the long term (e.g. by reducing the number of corneal transplantations).

Whether a screening program would result in sufficient net benefit for the population to justify

the program, will likely be country-dependent. Further research regarding the feasibility and

cost-effectiveness of keratoconus screening programs is needed.

28

Dutch summary

Doelstelling: Onderzoeken of screenen naar keratoconus aangewezen en nodig is, rekening

houdend met de huidige evidentie omtrent vroege detectie en behandeling. De criteria voor

verantwoorde screening, zoals opgesteld door Wilson en Jungner voor de

Wereldgezondheidsorganisatie, worden hiervoor als leidraad gebruikt.

Methode: Een systematische review van de Pubmed, Cochrane en Web of Science

databanken.

Resultaten: Recente artikels tonen aan dat de prevalentie van keratoconus aanzienlijk hoger

is dan voorheen werd gedacht. Hoewel keratoconus niet leidt tot blindheid, heeft het wel een

belangrijke impact op de levenskwaliteit van veelal jonge en economisch actieve patiënten. De

impact van keratoconus op het leven van patiënten is groter dan in eerste instantie gedacht

wordt, wanneer men louter zou afgaan op de prevalentie en klinische ernst. Zodoende heeft

keratoconus een niet te onderschatten financiële en economische impact, zowel binnen als

buiten de gezondheidszorg.

Methodes voor corneale beeldvorming, waaronder topografie, zijn de laatste decennia

geoptimaliseerd; en zijn in staat keratoconus te diagnosticeren in een subklinisch stadium. Het

ultieme behandeldoel is de visus van keratoconuspatiënten zolang als mogelijk te vrijwaren of

zelfs te verbeteren, en als dusdanig de impact op hun levenskwaliteit zo beperkt mogelijk te

houden. Hoewel er tot heden geen definitieve behandeling mogelijk is, betekende de

ontwikkeling van corneale cross-linking een ware revolutie in de zorg voor

keratoconuspatiënten. In het verleden waren enkel behandelopties voorhanden om het zicht van

keratoconuspatiënten te verbeteren (zoals brillen, contactlenzen, of hoornvliestransplantaties),

maar dankzij cross-linking kan de progressie van keratoconus nu afgeremd of zelfs gestopt

worden. Studies tonen aan dat cross-linking inderdaad leidt tot een vermindering van het aantal

hoornvliestransplantaties, en dat het bovendien een kosteneffectieve behandeling is.

Conclusie: Vroege detectie van keratoconus is primordiaal; opdat de voordelen van

stabilisatie van progressieve ziekte (dankzij cross-linking) optimaal benut kunnen worden.

Programma’s ter screening naar keratoconus zijn op heden niet geïmplementeerd, en onderzoek

naar dergelijke programma’s is schaars. Er zijn onvoldoende gegevens beschikbaar om in te

schatten of screening naar keratoconus een gunstige kosten-batenanalyse zou hebben. Verder

29

onderzoek in dit gebied is dan ook aangewezen teneinde het gebruik van cross-linking te

optimaliseren.

Addendum 1: Search strategy

Pubmed search last updated on 23/02/2019: English, keratoconus AND (screening OR cost OR

cost-effectiveness OR epidemiology OR natural course OR quality of life), excluding articles

on diagnosis only by adaptation of advanced search details to:

("keratoconus"[MeSH Terms] OR "keratoconus"[All Fields]) AND (("screening"[All Fields]

OR "mass screening"[MeSH Terms] OR ("mass"[All Fields] AND "screening"[All Fields]) OR

"mass screening"[All Fields] OR "screening"[All Fields] OR ("early"[All Fields] AND

"detection"[All Fields]) OR "early detection"[All Fields]) OR ("economics"[Subheading] OR

"economics"[All Fields] OR "cost"[All Fields] OR "costs and cost analysis"[MeSH Terms] OR

("costs"[All Fields] AND "cost"[All Fields] AND "analysis"[All Fields]) OR "costs and cost

analysis"[All Fields]) OR ("cost-benefit analysis"[MeSH Terms] OR ("cost-benefit"[All

Fields] AND "analysis"[All Fields]) OR "cost-benefit analysis"[All Fields] OR ("cost"[All

Fields] AND "effectiveness"[All Fields]) OR "cost effectiveness"[All Fields]) OR

("epidemiology"[Subheading] OR "epidemiology"[All Fields] OR "epidemiology"[MeSH

Terms]) OR (natural[All Fields] AND course[All Fields]) OR ("quality of life"[MeSH Terms]

OR ("quality"[All Fields] AND "life"[All Fields]) OR "quality of life"[All Fields]))

PRISMA 2009 Flow Diagram

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-

Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit www.prisma-statement.org.

Records identified through database searching

(n = 593 )

Scre

enin

g In

clu

ded

El

igib

ility

Id

enti

fica

tio

n

Additional records identified through other sources

(n = 65 )

Records screened (n = 658 )

Records excluded (n = 410)

Full-text articles assessed for eligibility

(n = 248 )

Full-text articles excluded, with reasons (cfr

addendum 2 – JBI CAT) (n = 61 )

Studies included in qualitative synthesis

(n = 187 )

Records after duplicates removed (n = 658 )

http://www.consort-statement.org/

Addendum 2: JBI Critical Appraisal Tool for Quality assessment of articles

Example of JBI appraisal tool, applied for prevalence/incidence studies

Using JBI Critical Appraisal Checklist for Studies

Reporting Prevalence Data

Munn Z, Moola S, Lisy K, Riitano D, Tufanaru

C. Methodological guidance for systematic

reviews of observational epidemiological studies

reporting prevalence and incidence data. Int J

Evid Based Healthc. 2015;13(3):147–153.

Aut

hor

Titl

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A)

Q4:

Wer

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subj

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ail?

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cond

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over

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cal a

naly

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iels

en, S

., Ra

mla

u-H

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n, C

. H.,

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sen,

A.,

Plan

a-Ri

poll,

O. a

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raph

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YY

YY

YY

U/N

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Ass

iri,

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., Yo

usuf

, B. I

., Q

uant

ock,

A. J

. and

Mur

phy,

P. J

.In

cide

nce

and

seve

rity

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erat

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audi

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2005

YY

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/NA

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NU

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/NA

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a, I.

, Ath

erle

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. and

Jam

es, N

. J.

Infl

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A.,

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, E.,

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., Ch

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., Bl

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isk

Fact

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surg

ery

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rofa

re, N

.J. :

199

5)20

16Y

YN

YY

YY

U/N

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A

Geo

rgio

u, T

., Fu

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l, C.

L.,

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els-

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n, A

. and

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, R.

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U/N

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God

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, G. A

., U

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l, C.

S.,

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f, S

. M. a

nd W

isse

, R. P

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of K

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ocon

us: A

Nat

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mer

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jour

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mol

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2017

YY

YY

YY

U/N

AU

/NA

YY

Gok

hale

, N. S

.Ep

idem

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atoc

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ort r

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., Sh

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, A.

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., H

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s : t

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sh C

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ge o

f Oph

thal

mic

Opt

icia

ns (O

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2018

YY

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YY

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Has

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., Kh

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., N

orou

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., A

man

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., M

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2014

YY

NY

YY

YU

/NA

YY

Jona

s, J.

B.,

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gia,

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in, A

., Ku

lkar

ni, M

. and

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jwan

i, K.

Prev

alen

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ssoc

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ons

of k

erat

ocon

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rura

l mah

aras

htra

in c

entr

al In

dia:

the

cent

ral I

ndia

eye

and

med

ical

stu

dyA

mer

ican

jour

nal o

f oph

thal

mol

ogy

2009

No

topo

grap

hy!

YY

YY

YY

NN

YY

Kenn

edy,

R. H

., Bo

urne

, W. M

. and

Dye

r, J.

A.

A 4

8-ye

ar c

linic

al a

nd e

pide

mio

logi

c st

udy

of k

erat

ocon

usA

mer

ican

jour

nal o

f oph

thal

mol

ogy

1986

YY

NU

/NA

YY

YU

/NA

YY

Mill

odot

, M.,

Shne

or, E

., A

lbou

, S.,

Atl

ani,

E. a

nd G

ordo

n-Sh

aag,

A.

Prev

alen

ce a

nd a

ssoc

iate

d fa

ctor

s of

ker

atoc

onus

in Je

rusa

lem

: a c

ross

-sec

tion

al s

tudy

Oph

thal

mic

epi

dem

iolo

gy20

11N

o V

A re

port

edY

YY

NY

YY

YY

U/N

A

Nie

lsen

, K.,

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rtda

l, J.

, Aag

aard

Noh

r, E

. and

Ehl

ers,

N.

Inci

denc

e an

d pr

eval

ence

of k

erat

ocon

us in

Den

mar

kA

cta

opht

halm

olog

ica

Scan

dina

vica

2007

Esti

mat

ion

base

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pita

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ords

YY

U/N

AY

YY

U/N

AU

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NU

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Ow

ens,

H. a

nd G

ambl

e, G

.A

pro

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us in

New

Zea

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Corn

ea20

03Y

YY

NY

YY

YY

U/N

A

Pear

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A. R

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Sarv

anan

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nd S

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ord-

Smit

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H.

Doe

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ori

gin

infl

uenc

e th

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cide

nce

or s

ever

ity

of k

erat

ocon

us?

Eye

(Lon

don,

Eng

land

)20

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YN

U/N

AY

YU

/NA

U/N

aY

U/N

A

Reev

es, S

. W.,

Ellw

ein,

L. B

., Ki

m, T

., Co

nsta

ntin

e, R

. and

Lee

, P. P

.Ke

rato

conu

s in

the

Med

icar

e po

pula

tion

Corn

ea20

09Y

YY

YN

YU

/NA

U/N

AY

U/N

A

Rive

ra, L

. and

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, S. D

.Ke

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de la

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ica

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uert

o Ri

co20

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ava

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es N

etto

, E. A

., A

l-O

taib

i, W

. M.,

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ezi,

N. L

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ing,

S.,

Al-

Farh

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. M.,

Rand

lem

an, J

. B. a

nd H

afez

i, F.

Prev

alen

ce o

f ker

atoc

onus

in p

aedi

atri

c pa

tien

ts in

Riy

adh,

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di A

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itis

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ion

YY

YY

YY

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/NA

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., Ja

fari

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. R.,

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. A.,

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mia

n, F

., Po

orsa

lman

, H.,

Mah

davi

, M.,

Shoj

a, M

. R. a

nd K

atib

eh, M

.Ep

idem

iolo

gy o

f ker

atoc

onus

in a

n Ir

ania

n po

pula

tion

Corn

ea20

12Y

YY

YY

YY

YY

Y

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Is early detection of keratoconus worthwhile? Systematic ...€¦ · Organization principles of screening are used as a guideline. Methods: A systematic review of the Pubmed, Cochrane